N-Thiazolyl-5,6-dihydro-4-oxo-4H-thieno[2,3-b]thiopyran-5-carboxamides

ABSTRACT

This invention relates to 5,6-dihydro-4-oxo-4H-thieno[2,3-b]thiopyran-5-carboxamides of the Formula I: ##STR1## wherein R 1  is hydrogen, halogen or lower alkyl; R 2  is hydrogen, lower alkyl or aryl; and Ar is aryl or heterocyclic; their pharmaceutically acceptable salts and to processes for their preparation. The compounds of this invention exhibit antibacterial, antifungal and antiallergy activity.

This is a division of application Ser. No. 749,507 filed Dec. 10, 1976.

DESCRIPTION OF THE INVENTION

This relates to novel5,6-dihydro-4-oxo-4H-thieno[2,3-b]thiopyran-5-carboxamides of theFormula I: ##STR2## wherein R₁ is hydrogen, halogen or lower alkyl; R₂is hydrogen, lower alkyl or aryl; Ar is aryl or heterocyclic; and theirpharmaceutically acceptable salts.

This invention also includes within its scope novel processes forpreparing the above compounds as well as intermediates employed in theirsynthesis.

The compounds of the Formula I are prepared by the following sequence:Reaction of a compound of the Formula II: ##STR3## wherein R₁ and R₂ areas defined above in Formula I, with a sodium alkoxide and a(dialkyl)oxalate to give a compound of the Formula III: ##STR4## whereinR₁ and R₂ are as defined above in Formula II and R' is lower alkyl. Inaforementioned reaction, the alkyl group in the sodium alkoxide may varybut must be the same as the alkyl groups in the oxalate diester.Typically, sodium methoxide and dimethyl oxalate are used.

Compound III is then subjected to decarbonylation at 170° C. to 180° C.in the presence of powdered glass, to obtain a compound of the FormulaIV: ##STR5## wherein R₁, R₂ and R' are as defined above in Formula III.

Compound IV is reacted with an appropriate amine in a suitable highboiling solvent such as xylene to obtain the desired Compound I. Amineshaving the formula:

    NH.sub.2 --Ar

are suitable for use in this last mentioned reaction, wherein Ar is amonocyclic aromatic hydrocarbon; a substituted monocyclic aromatichydrocarbon wherein the substituent may be halogen, lower alkoxy,trifluoromethyl and the like; a monocyclic heterocycle; or a substitutedmonocyclic heterocycle wherein the substituent may be halogen, loweralkoxy, trifluoromethyl and the like. Typical amines include aniline,amino-substituted pyridine, amino-substituted isoxazole,amino-substituted thiazole and the like.

The starting material II (5,6-dihydro-4H-thieno[2,3-b]-thiopyran-4-one,R₁ = R₂ = H), is prepared according to the procedure of P. Cagniant andMme. Densie Cagniant, Bull. Soc. Chim. Fr., 2172 (1966) or by achemically known, obvious variation of this procedure.

The compounds of this invention exhibit antibacterial, antifungal andantiallergy activity. Compounds of the Formula I show antibacterial andantifungal activity. For example,5,6-dihydro-N-(5-methyl-3-ixoxazolyl)-4-oxo4H-thieno[2,3-b]-thiopyran-5-carboxamideis active against fungi such as C. albicans and T. mentagrophytes,showing minimum inhibitory concentrations in the range of 125 to 1000mcg/ml, when evaluated in the in vitro tube dilution procedure describedin U.S. Pat. No. 3,651,216. Thus, these compounds are useful in thetreatment of fungal infections. The novel antibacterial, antifungalsubstances of this invention can be formulated with inert excipientsinto various dosage forms for oral, parenteral and topicaladministration by methods well-known to those skilled in thepharmacist's art. Tablets, capsules, powders, solutions, suspensions,ointments, gels and creams are included among the suitable dosage forms.

Compounds of the invention having the Formula III are active inprevention of allergic and asthmatic reactions in rats at dose levels of25 to 100 mg/kg. Thus methyl4-4-hydroxy-α-oxo-6H-thieno[2,3-b]thiopyran-5-acetate shows a 49%inhibition of the allergic response at 25 mg/kg when testedintraperitoneally in the passive cutaneous anaphalaxis (PCA) screen,which is a modification of procedures described by I. Mota, LifeSciences, 7:465 (1963) and Z. Ovary and O. Bier, Proc. Soc. Exptl. Biol.Med., 81:585 (1952). Consequently, they may be useful in the treatmentof asthma, hay fever and other allergic conditions.

The compounds of this invention having Formula III can be administeredorally or parenterally as aqueous suspensions or as aqueous solutions oftheir alkali metal salts.

Compounds of the invention having the Formula IV are useful asintermediates to sythesize4-hydroxy-6H-thieno[2,3-b]thiopyran-5-carboxamides 7,7-dioxide whichshow antiinflammatory activity. The preparation and the activity of4-hydroxy-6H-thieno[2,3-b]thiopyran-5-carboxamides 7,7-dioxides are thesubject of copending U.S. Applicaton Ser. No. 749,491 filed Dec. 10,1976 by Jagadish C. Sircar, Stephen J. Kesten and Harold Zinnes,entitled "Amides of 4-Hydroxy-6H-Thieno[2,3-b]Thiopyran-5-CarboxylicAcid-7,7-Dioxide and Process for the Preparation Thereof".

The following definitions apply to all of the compounds, intermediatesand processes of this invention: lower alkyl is meant to include 1 to 7carbon, preferably 1 to 4 carbon, straight or branched alkyl chains;aforementioned definition of lower alkyl applies to the alkyl portion ofthe term lower alkoxy and to the alkyl portion of the term alkoxide;halogen is meant to include chlorine, bromine and iodine; aryl is meantto include monocyclic aromatic hydrocarbons; substituted monocyclicaromatic hydrocarbons wherein the substituent may be halogen, loweralkoxy, trifluoromethyl and the like; monocyclic heterocycles; andsubstituted monocyclic heterocycles wherein the substituent may behalogen, lower alkoxy, trifluoromethyl and the like.

In order to further illustrate this invention, the following examplesare provided:

EXAMPLE 1 ##STR6##Methyl-4-hydroxy-α-oxo-6H-thieno[2,3-b]-thiopyran-5-acetate

A mixture of sodium methoxide (21.6 g, 0.4 mole) and dimethyloxalate(47.2 g, 0.4 mole) in benzene (300 ml) is refluxed for 5 min. in orderto dissolve most of the solid. To the cooled solution is added asolution of 5,6-dihydro-4H-thieno[2,3-b]-thiopyran-4-one (34 g, 0.2mole) in benzene (300 ml) and the mixture is stirred for 3 hrs. to givea yellow suspension. The mixture is poured into ice-water mixture (1750ml). After separating the aqueous layer from the benzene layer, thebenzene layer is extracted with 1(N) NaOH solution (250 ml), and thecombined aqueous solution is washed once with ether (100 ml) andacidified with (N) HCl. The yellow crystalline glyoxalate is filteredoff and dried over P₂ O₅ to give 45.8 g (91%) of the desired product;m.p. 53°-56° C. IR (CHCl₃) 3120-3040 (b, OH), 1735 (C═O), 1605 (C═C-C═O)cm⁻¹. NMR (CDCl₃) δ 10.6 (s, 1, OH, exchangeable); 7.35 (d, 1, C₂ );7.05 (d, 1, C₃); 4.4 (s, 2, C₆ ); 3.9 (s, 3, OCH₃). λ_(max) ^(EtOH) 320(5,600), 238 (10,800) mμ

Anal. Calcd. for C₁₀ H₈ O₄ S₂ : C, 46,86; H, 3.15; S, 25.02. Found: C,46.92; H, 3.23; S, 24.58, 24.64.

EXAMPLE 2 ##STR7## Methyl5,6,-dihydro-4-oxo-4H-thieno[2,3-b]thiopyran-5-carboxylate

A mixture of methyl4-hydroxy-α-oxo-6H-thieno[2,3-b]-thiopyran-5-acetate(71 g) and powderedglass (71 g) is heated at 180° C. for 25 min. when a vigorous evolutionof CO takes place. After cooling, the dark product is dissolved inmethylene chloride and filtered from the glass, and the filtrateevaporated to dryness. The dark brown solid residue is dissolved in dryether (2500 ml) and filtered through alumina column (3 × 13 cm²). Thecolumn is washed with additional amount of dry ether (250 ml) and thetotal ethereal solution is slowly concentrated until the crystals startsto form. The crystals are recovered, triturated with ether and filteredto give white solid (38.2 g, 60%), m.p. 94°-97° C. IR (CHCl₃) 1742(C═O), 1673 (C═O) cm⁻¹. NMR (CDCl₃) δ 7.5 (d, 1, C₂), 7.0 (d, 1, C₃),3.65 (m, 6, OCH₃, C₅ and C₆). λEtOH/max 332 (4,000), 261 (9,000), 240(18,000).

Anal. Calcd. for C₉ H₈ O₃ S₂ : C, 47.35; H, 3.53; S, 28.09. Found: C,47.25; H, 3.53; S, 27.96, 28.05.

EXAMPLE 3 ##STR8## Amides of5,6-dihydro-4-oxo-4H-thieno[2,3-b]thiopyran-5-carboxylic acid.

General Procedure: A mixture of methyl5,6-dihydro-4-oxo4H-thieno[2,3-b]-thiopyran-5-carboxylate (5.7 g, 0.025mole), an appropriate amine (0.0375 moles) and xylene (180 ml) isrefluxed for 2.5 to 3 hrs. in a Soxhlet apparatus, the thimble of whichcontains 20 g of Linde type 4A molecular sieve. The mixture is cooledand the resulting crystalline product is collected and recrystallized.

EXAMPLE 4 ##STR9##5,6-Dihydro-4-oxo-N-phenyl-4H-thieno[2,3-b]-thiopyran-5-carboxamide

A mixture of methyl5,6-dihydro-4-oxo-4H-thieno[2,3-b]-thiopyran-5-carboxylate (5.7 g, 0.025mole), aniline (3.5 g, 0.0375 mole) and xylene (180 ml) is refluxed for2.5 hrs. in a Soxhlet apparatus, the thimble of which contains 20 g ofLinde type 4A molecular sieve. The mixture is cooled in an ice bath, andthe resulting crystalline precipitate (m.p.155°-158° C.) is collected,dried and recrystallized from methylene chloride and isopropyl ether togive 6.5 g (90%) of off-white crystalline material, m.p. 155°-158° C.

IR (CHCl₃) 3300 (broad, NH), 1690 (C═O), 1648 (C═O), 1603 (CONH) cm⁻¹.

NMR (CDCl₃) δ 9.4 (b, 1, NH), 7.6-6.9 (m, 7, aromatic), 3.65 (m, 3, C₅,C₆). λ_(max) ^(EtOH) 330 (4,000), 242 (32,400) mμ

Anal. Calcd. for C₁₄ H₁₁ NO₂ S₂ : C, 58.11; H, 3.83; N, 4.84; S, 22.16.Found: C, 58.34; H, 4.01; N, 4.88; S, 22.41, 22.38.

EXAMPLE 5 ##STR10##5,6-Dihydro-N-(5-methyl-3-isoxazolyl)-4-oxo-4H-thieno[2,3-b]-thiopyran-5-carboxamide

This product is obtained by using 3-amino-5-methyl-isoxazole, followingthe procedure of Example 3. It is recrystallized from methylene chlorideand isopropylether mixture. Yield 5.9 g (80%), m.p. 143°-146° C.

IR (CHCl₃) 3400-3200 (b, NH); 1705 (C═O); 1655 (C═O); 1625 (CONH) cm⁻¹.

NMR (CDCl₃) δ 10.1 (b, 1, NH); 7.5 (d, 1, C₂); 7.05 (d, 1, C₃); 6.67 (s,1H, C₄ '); 3.8 (m, 3, C₅, C₆); 2.4 (s, 3, C₅ '--CH₃). λ_(max) ^(EtOH)238 (27,200) mμ

Anal. Calcd. for C₁₂ H₁₀ N₂ O₃ S₂ : C, 48.97; H, 3.42; N, 9.52; S,21.79. Found: C, 48.88; H, 3.48; N, 9.56; S, 21.66, 21.73.

EXAMPLE 6 ##STR11##5,6-Dihydro-4-oxo-N-(2-thiazolyl)-4H-thieno[2,3-b]-thiopyran-5-carboxamide

This product is obtained by using 2-amino-thiazole, following theprocedure of Example 3. It is recrystallized from methanol. Yield 6.0 g(81%), m.p. 201°-203° C.

IR (Nujol) 3200-3120 (broad, NH); 1665 (C═O); 1580 (CONH) cm⁻¹.

NMR (DMSO) δ 12.35 (b, 1, NH); 7.4 (m, 4, aromatic); 4.0 (m, 3H, c₅,C₆--). λ_(max) ^(EtOH) 266 (16,000); 240 (18,000) mμ

Anal. Calcd. for C₁₁ H₈ N₂ O₂ S₃ : C, 44.58; H, 2.72; N, 9.45; S, 32.45.Found: C, 44.52; H, 2.77; N, 9.36; S, 32.56, 32.74.

We claim:
 1. A compound of the Formula I: ##STR12## wherein R₁ ishydrogen, halogen or lower alkyl; R₂ is hydrogen, lower alkyl or phenyl;and Ar is thiazolyl; or its pharmaceutically acceptable salts.
 2. Acompound according to claim 1 which is5,6-dihydro-4-oxo-N-(2-thiazolyl)-4H-thieno[2,3-b]-thiopyran-5-carboxamide.